Background: Increased production of immune response mediators by mononuclear cells is frequently observed after starting HAART. Cytokines endowed with anti-insulin activity may contribute to some metabolic derangements, such as insulin resistance, glucose intolerance, and indirectly to hypertryglyceridemia or body shape changes. Aim of the study: to correlate variations of anthropometric indexes, insulin resistance, and blood lipids with immune response parameters such as early intracellular TNF-a and IFN-g production, T-CD4 increase, and with virological response, in a cohort of ARV-naïve HIV patients before starting HAART and followed during treatment for no less than 52 weeks. Methods: Body mass index (BMI) and waist-hip ratio (WHR); plasma glucose, insulin, cortisol, triglycerides, cholesterol (total / LDL) levels, and HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) were evaluated in 21 consecutive HIV+ adults (median age: 35 yrs, range 22-47; 18 male, 3 female; 10 MSM, 6 hetero; 5 ex-IDUs) at baseline and 4, 8, 12, 24, 36 and 52 wks after starting treatment including 2 NRTI plus either a NNRTI (10 pts) or a PI (11 pts). Intracellular TNF-a and IFN-g were evaluated at above times on PBMCs by flow cytometry with monoclonal antibodies (Becton-Dickinson); absolute numbers of positive cells/mL were calculated. Results: Mean baseline CD4 cells (198±220/mL) increased to 470±376 and to HIV RNA was undetectable (< 50 c/mL) in at 12 wks, at 24 wks, and at end of follow-up. Significant increases compared to baseline (ANOVA for repeated measures with Tukey’s pairwise comparisons) were observed for insulin at wk 8 (13.8±9 compared to 8.2±4 mU/L, p=0.05), triglycerides at wk 12 (185 ±126 compared to 120 ± 41mg/dL, p=0.05), total cholesterol at wk 12 (225±41 compared to 175±22 mg/dL, p=0.007), TNF-a and IFN-g at wk 12 (respectively 4477±3641 compared to 1182±607, and 5243 ± 2035 compared to 1721±619 positive cells/mL, p=0.009 and 0.05), while baseline glucose (84±13 mg/dL), and cortisol (11±9mg/dL) levels did not change significantly. Patients with early increase (> 2 x S.E.M. at 12 weeks) of IFN-g and TNF-a positive PBMCs showed, compared to those without variations, higher insulin levels (19 ±12 mU/L vs 7±3,2, p<0.05 by t-test), HOMA-IR (4.8 ±5 vs 1,7±1, p=0.05 by t-test), WHR (0,99 ± 0.05 vs 0,85 ± 0.04, p<0,001), BMI (26 ± 3.8 vs 21,8 ± 1.7, p=0,032) at 24 wks, and respectively higher WHR (1 ± 0.36 vs 0.84 ± 0.6, p=0,006) and BMI at 52 weeks. Early HOMA-IR increase was also associated with higher triglyceride levels (257 ±129 vs 146 ± 118, p=0.05) at end of follow-up compared with no increase. None among other possible factors, such as treatment (PI-based vs PI-sparing), CD4 cell variations or time to undetectable viral load was associated with metabolic changes. Conclusions: In a cohort of ART-naïve patients followed for 52 weeks, early increase in IFN-g and TNF-a are associated with insulin resistance, later increase in triglyceride plasma levels, and with significant modifications of anthropometric (WHR and BMI) indexes between 24 and 52 weeks after starting HAART. Further prospective studies with longer follow-up are needed in order to correlate the observed changes with more significant modifications of body fat distribution.
Alterations of anthropometric and metabolic parameters correlate with early increase in IFN-g and TNF-a production after starting antiretroviral treatment in ART-naive HIV patients
BIGLINO, Alberto;
2006-01-01
Abstract
Background: Increased production of immune response mediators by mononuclear cells is frequently observed after starting HAART. Cytokines endowed with anti-insulin activity may contribute to some metabolic derangements, such as insulin resistance, glucose intolerance, and indirectly to hypertryglyceridemia or body shape changes. Aim of the study: to correlate variations of anthropometric indexes, insulin resistance, and blood lipids with immune response parameters such as early intracellular TNF-a and IFN-g production, T-CD4 increase, and with virological response, in a cohort of ARV-naïve HIV patients before starting HAART and followed during treatment for no less than 52 weeks. Methods: Body mass index (BMI) and waist-hip ratio (WHR); plasma glucose, insulin, cortisol, triglycerides, cholesterol (total / LDL) levels, and HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) were evaluated in 21 consecutive HIV+ adults (median age: 35 yrs, range 22-47; 18 male, 3 female; 10 MSM, 6 hetero; 5 ex-IDUs) at baseline and 4, 8, 12, 24, 36 and 52 wks after starting treatment including 2 NRTI plus either a NNRTI (10 pts) or a PI (11 pts). Intracellular TNF-a and IFN-g were evaluated at above times on PBMCs by flow cytometry with monoclonal antibodies (Becton-Dickinson); absolute numbers of positive cells/mL were calculated. Results: Mean baseline CD4 cells (198±220/mL) increased to 470±376 and to HIV RNA was undetectable (< 50 c/mL) in at 12 wks, at 24 wks, and at end of follow-up. Significant increases compared to baseline (ANOVA for repeated measures with Tukey’s pairwise comparisons) were observed for insulin at wk 8 (13.8±9 compared to 8.2±4 mU/L, p=0.05), triglycerides at wk 12 (185 ±126 compared to 120 ± 41mg/dL, p=0.05), total cholesterol at wk 12 (225±41 compared to 175±22 mg/dL, p=0.007), TNF-a and IFN-g at wk 12 (respectively 4477±3641 compared to 1182±607, and 5243 ± 2035 compared to 1721±619 positive cells/mL, p=0.009 and 0.05), while baseline glucose (84±13 mg/dL), and cortisol (11±9mg/dL) levels did not change significantly. Patients with early increase (> 2 x S.E.M. at 12 weeks) of IFN-g and TNF-a positive PBMCs showed, compared to those without variations, higher insulin levels (19 ±12 mU/L vs 7±3,2, p<0.05 by t-test), HOMA-IR (4.8 ±5 vs 1,7±1, p=0.05 by t-test), WHR (0,99 ± 0.05 vs 0,85 ± 0.04, p<0,001), BMI (26 ± 3.8 vs 21,8 ± 1.7, p=0,032) at 24 wks, and respectively higher WHR (1 ± 0.36 vs 0.84 ± 0.6, p=0,006) and BMI at 52 weeks. Early HOMA-IR increase was also associated with higher triglyceride levels (257 ±129 vs 146 ± 118, p=0.05) at end of follow-up compared with no increase. None among other possible factors, such as treatment (PI-based vs PI-sparing), CD4 cell variations or time to undetectable viral load was associated with metabolic changes. Conclusions: In a cohort of ART-naïve patients followed for 52 weeks, early increase in IFN-g and TNF-a are associated with insulin resistance, later increase in triglyceride plasma levels, and with significant modifications of anthropometric (WHR and BMI) indexes between 24 and 52 weeks after starting HAART. Further prospective studies with longer follow-up are needed in order to correlate the observed changes with more significant modifications of body fat distribution.
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